Iodixanol is the non-proprietory name of the chemical drug substance of a non-ionic X-ray contrast agent marketed under the trade name Visipaque™. Visipaque™ is one of the most used agents in diagnostic X-ray procedures and is manufactured in large quantities.
The manufacture of such non-ionic X-ray contrast agents involves the production of the chemical drug substance (referred to as primary production) followed by formulation into the drug product (referred to as secondary production). Primary production of iodixanol involves a multi step chemical synthesis and a thorough purification process. For a commercial drug product it is important for the primary production to be efficient and economical and to provide a drug substance fulfilling the specifications, e.g. as expressed on the US Pharmacopeia.
A number of methods are known for the preparation of iodixanol. These are all multi step chemical synthetic processes and the cost of the final formulated product thus mainly depends on these processes. It is therefore important to optimize the processes both for economic and environmental reasons.
Three main chemical synthetic processes are known for the preparation of iodixanol, all of which start with 5-nitroisophthalic acid. In the first process described in EP patent 108638, which document is hereby incorporated by reference, the final intermediate 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide (hereinafter “Compound A”) is reacted with a dimerisation agent such as epichlorohydrin to yield the drug substance, see Scheme I.

The overall yield in this process is relatively low and the purification of the end product iodixanol is expensive and time consuming. The purification process described in EP patent 108638 involves purification by preparative liquid chromatography. The use of preparative liquid chromatography is a serious disadvantage in industrial processes in particular due to the high costs involved.
Several attempts have been made to find alternative manufacturing processes. Attempts to increase the yield of the chemical synthesis is published by
Priebe et. al. (Acta Radiol. 36 (1995), Suppl. 399, 21-31). This publication describes another route which avoids the difficult last step of the process of Scheme I. However, the route involves eight reaction steps from 5-nitroisophthalic acid, which is undesirable, and one of the steps includes chlorination with thionyl chloride, which is extremely corrosive. Also, the introduction of the iodine atoms takes place very early in the sequence, which is disadvantageous as iodine is the most expensive reagent in the process. The yield and final purification method for this route have not been reported.
The third route to iodixanol involves the synthesis of 5-amino-2,4,6-triiodoisophthalic acid (WO 96/37458) and then its dichloride (WO 96/37459), followed by conversion into Compound A (U.S. Pat. No. 5,705,692) and finally dimerisation as in the process of Scheme I. This method thus has the same disadvantages as the first process, and also uses an undesirable acid chlorination step.
Several attempts have also been made to find alternative purification procedures avoiding the liquid chromatography method described in European patent 108636.
WO 99/18054 describes a process for the crystallization of i.a. iodixanol where the crystallization is effected with high thermal energy, specifically under elevated pressure and at a temperature above the boiling point of the solution at atmospheric pressure. A number of suitable solvents are listed at page 3 of the document, including C1-4 alcohols such as methanol and isopropanol (propan-2-ol, 2-propanol). A mixture of methanol and propan-2-ol is noted as the preferred solvent according to this invention.
WO 2007/013815 describes a continuous crystallization process of iodixanol where using a solvent mixture comprising methanol/water/2-propanol is described.
WO 2006/016815 describes a process for the crystallization of iodixanol with 1-methoxy-2-propanol as solvent.
WO 2007/064220 describes a process for the crystallization of iodixanol with ethanol as solvent.
WO 2007/073202 describes a process for the crystallization of iodixanol with n-propanol as solvent.
It is hence a desire to identify a purification process wherein crude iodixanol as obtained by N-alkylation of Compound A as illustrated in Scheme I, and hereinafter denoted “dimerisation”, can be obtained in a sufficiently pure form preferably by one single crystallization step. The requirements to such process are: The total crystallization time should be shortened and should not exceed 4 days. It is further desirable to achieve a more cost-efficient purification process by reducing the energy input and reducing the amounts of solvents needed in the process, in addition to achieve a higher output of product per unit reactor volume.
The purity of the crude iodixanol is typically only 83-84%, which means that the purification effect in the crystallisation needs to be very good to yield a product within the quality requirements. At the same time iodixanol is produced in large quantities, so the yield in the process is very important in terms of financial performance.
The crude iodixanol from the preceeding process step is dissolved in water before the crystallisation step. This is a challenge, since even small amounts of water in the mother liquor of the crystallisation increases the solubility of iodixanol significantly. We have now surprisingly found that minimization of the water content in the mother liquor combined with gradual addition of isopropanol during the crystallisation overcomes this problem.
Hence, it has now surprisingly been found that using a solvent mixture comprising water, methanol and isopropanol in the purification step of crude iodixanol will fulfill one or more of the requirements listed above.